Pyruvate carboxylase (PC) is a biotin-activated mitochondrial enzyme that is involved in the formation of the tricarboxylic acid cycle intermediate, oxaloacetate. A primary deficiency of the enzyme is an autosomal recessive condition with three clinical variants that affects neonates, infants and older children. The early-onset forms can cause sudden infant death and are sometimes referred to as Leigh's syndrome. The disease is accompanied by metabolic disturbances (hypoglycemia, hyperammonemia and lactic acidosis) and mainly affects myelin formation and brainstem function. We identified of a T->C substitution at nucleotide 472 (GenBank acc. no. U04641) in a family with partial PC enzyme activity and dysmyelination. This missense mutation causes a valine to alanine substitution at amino acid residue 145 in the enzyme's biotin carboxylase domain. The clinical response to high doses of biotin may be related to enhanced stability of the mutant protein or increased enzymatic activity of the residual protein.